Salina Gairhe, BSC, MSc, MSc, PhD

Summary of Research Project:

1. What is the major problem being addressed by this study?Pulmonary hypertension is a debilitating disease with no effective therapeutic option. Current medical treatment improves symptoms and survival, but the morbidity and mortality remains unacceptably high. This suggests that cellular and molecular pathogenic mechanisms of PAH is neither been identified nor therapeutically targeted. A major hallmark of PAH are sustained vasoconstriction, arterial wall thickening, and in situ thrombosis. There is substantial evidence that the sustained pulmonary vasoconstriction is due predominantly to RhoA/Rho kinase-signaling. This study will address that phospholipid, sphingosine-1-phosphate (SIP) is an upstream mediator of Rho kinase signaling that promotes pulmonary vascular vasoconstriction associated with pulmonary arterial hypertension.

* 2. What specific questions are you asking and how will you attempt to answer them? We will examine the possible role of S1P and its source in the sustained vasoconstriction and increased tone associated with PAH. We will use lungs perfused with saline and pulmonary arteries isolated from Sugen5416/hypoxia/normoxia rat model, the only rodent model of PAH that recapitulates human disease with plexiform lesions. First we will use pharmacologic inhibitors to determine the role of Rho kinase signaling in SIP-induced vasoconstriction. Second we will determine the source of S1P in PAH by performing similar studies using whole and depleted blood perfusates. Third, results from these studies will be used to direct in vivo studies that will administer anti-S1P agents to PAH rats and examine vasodilator effects.

* 3. What is the long-term biomedical significance of your work, particularly as it pertains to the cardiovascular area? What major therapeutic advance(s) do you anticipate that it will lead to? For instance, new drug(s), a surgical technique/procedure, a diagnostic tool/test, a previously undetected risk factor, etc.There is limited ability to effectively improve survival of patients with PAH and the molecular mechanism linked with pulmonary artery dysfunction is poorly understood. If the results of the study are positive, this would provide insight into whether S1P signaling contributes to sustained vasoconstriction and increased tone associated with PAH via Rho kinase activation. Positive results will stimulate considerable additional research to determine if S1P signaling pathway is also important in the pathogenesis of human PAH and, if so, the mechanisms of its regulation can be therapeutically

Salina Gairhe, Sarah Sayner, 2010. Did you know that woman with pulmonary arterial hypertension (PAH) have an elevated risk of mortality during pregnancy? Online article, Center for Lung Biology, University of South Alabama. “http://www.southalabama.edu/clb/index.htm”.

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